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Translational Cancer Research Sep 2019Osteosarcoma is a primary malignant bone tumor that frequently occurs in adolescents and children, its high aggressiveness and rapid metastasis often resulting in poor...
BACKGROUND
Osteosarcoma is a primary malignant bone tumor that frequently occurs in adolescents and children, its high aggressiveness and rapid metastasis often resulting in poor prognoses. In previous studies, Prazosin has been shown to possess anti-proliferative properties against prostate cancer and glioblastoma cells. In our study, we investigated Prazosin's underlying mechanisms and its effects on the biological behaviors of osteosarcoma cells.
METHODS
Osteosarcoma cell lines MG63 and 143B were treated with different concentrations of Prazosin, and a CCK8 assay assessed its effect on cell viability. Colony formation, Transwell and flow cytometry assays were used to examine its effects on cell proliferation, cell migration, and cell invasion and apoptosis, respectively. The expression of relevant proteins was then examined using western blotting.
RESULTS
Our data showed that Prazosin dose-dependently reduced the viability of MG63 and 143B cells and significantly inhibited their clonogenic ability. Moreover, Prazosin attenuated the cell migration and invasion abilities of MG63 and 143B cells when compared with the NC group. It also accelerated cell apoptosis in mitochondrial pathways by regulating Bcl-2/Bax axis and caspase 3. Furthermore, Prazosin treatment inactivated the Akt/mTOR pathway by down-regulating Akt and mTOR phosphorylation (p-Akt, p-mTOR) and the expression of P70 and cyclin D1.
CONCLUSIONS
Our data highlights the fact that Prazosin inhibits cell growth, inhibits the motility of osteosarcoma cells, and promotes apoptosis, suggesting that Prazosin is a potential anti-cancer agent in osteosarcoma therapy.
PubMed: 35116948
DOI: 10.21037/tcr.2019.09.03 -
Journal of Clinical Hypertension... Sep 2022There is emerging evidence that α1-blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood... (Review)
Review
There is emerging evidence that α1-blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1-blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1-blockers as add-on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1-blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1-blockers have to be used under several considerations. Among the currently available agents, only long-acting α1-blockers, such as doxazosin gastrointestinal therapeutic system 4-8 mg daily and terazosin 2-4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1-blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1-blocker with a diuretic.
Topics: Adrenergic alpha-Antagonists; Aged; Aldosterone; Antihypertensive Agents; Diuretics; Doxazosin; Humans; Hypertension; Renin
PubMed: 36196467
DOI: 10.1111/jch.14556 -
American Journal of Alzheimer's Disease... May 2017The pathogenesis of Alzheimer's disease involves multiple pathways that, at the macrolevel, include decreased proliferation plus increased loss affecting neurons,... (Review)
Review
The pathogenesis of Alzheimer's disease involves multiple pathways that, at the macrolevel, include decreased proliferation plus increased loss affecting neurons, astrocytes, and capillaries and, at the subcellular level, involve several elements: amyloid/amyloid precursor protein, presenilins, the unfolded protein response, the ubiquitin/proteasome system, the Wnt/catenin system, the Notch signaling system, mitochondria, mitophagy, calcium, and tau. Data presented show the intimate, anatomical interactions between neurons, astrocytes, and capillaries; the interactions between the several subcellular factors affecting those cells; and the treatments that are currently available and that might correct dysfunctions in the subcellular factors. Available treatments include lithium, valproate, pioglitazone, erythropoietin, and prazosin. Since the subcellular pathogenesis involves multiple interacting elements, combination treatment would be more effective than administration of a single drug directed at only 1 element. The overall purpose of this presentation is to describe the pathogenesis in detail and to explain the proposed treatments.
Topics: Alzheimer Disease; Animals; Astrocytes; Brain; Capillaries; Drug Therapy, Combination; Humans; Neurons
PubMed: 28423937
DOI: 10.1177/1533317517698790 -
Therapeutic Advances in Endocrinology... Jul 2018Hyperglycaemia is often observed in severe scorpion-envenomed patients. It is due to a severe autonomic storm with a massive release of catecholamines, increased... (Review)
Review
Hyperglycaemia is often observed in severe scorpion-envenomed patients. It is due to a severe autonomic storm with a massive release of catecholamines, increased glucagon levels, cortisol levels, and either decreased insulin levels or insulin resistance. The presence of hyperglycaemia is an indicator of severity in this specific condition. Indeed, hyperglycaemia was associated with the severity of clinical manifestations of severe scorpion envenomation requiring intensive care unit (ICU) admission. In fact, the presence of hyperglycaemia was associated with the presence of respiratory failure, pulmonary oedema, haemodynamic instability, neurological failure, multisystem organ failure, and an increased mortality and ICU length of stay. As a consequence, we think the presence of hyperglycaemia in scorpion-envenomed patients at the emergency department prompts searching for presence of systemic manifestations or cardiorespiratory manifestations. As a consequence, the presence of hyperglycaemia can help screen severe patients at the emergency department. The current management of severe scorpion envenomation involves the admission and close surveillance in the ICU, where vital signs and continuous monitoring enable early initiation of therapy for life-threatening complications. The use of antivenom for scorpion stings remains controversial. All patients with pulmonary oedema should receive prazosin and possibly dobutamine, according the scorpion's species. Mechanical ventilation is usually used in severe cases. Insulin should be reserved for severe cases with confirmed excessive hyperglycaemia (>10 mmol/l).
PubMed: 29977498
DOI: 10.1177/2042018818772779 -
World Journal of Surgical Oncology Jun 2023Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors characterized by hemodynamic instability, caused by the paroxysmal release of...
BACKGROUND
Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors characterized by hemodynamic instability, caused by the paroxysmal release of catecholamines. Patients may develop cardiovascular complications in the perioperative phase due to the massive release of catecholamines, particularly during anesthetic induction and surgical manipulation of the tumor. The aim of this retrospective study was to evaluate the risk factors involved in perioperative hemodynamic instability in patients who underwent surgery for chromaffin tumors.
METHODS
Forty patients (median age 55 [36.50-64.50]) undergone surgery for PHEO/abdominal PGL from January 2011 to December 2016 at the AOU Careggi (Florence, Italy) were retrospectively evaluated. Systolic, diastolic, and mean blood pressure were considered at baseline and during surgery. Patients with blood pressure steadily < 140/90 mmHg before surgery were considered "adequately prepared". A preoperative therapy with doxazosin, a selective alpha-1 blocker, was started in all patients for at least 14 days prior to the surgery. The presence of hemodynamic instability was reported.
RESULTS
Comparing males and females, a significant difference in doxazosin daily dose (p = 0.018), systolic blood pressure (p = 0.048), and in the proportion of adequately prepared patients (p = 0.031) emerged. A positive correlation between preoperative daily dose of doxazosin, tumor size (B = 0.60, p < 0.001), and urinary normetanephrine levels (B = 0.64, p < 0.001) was also observed. Hemodynamic instability occurred in 30.0% of patients. The absence of adequate preparation (p = 0.012) before surgery, urinary normetanephrine levels (NMNur p = 0.039), and surgery time (minutes) (p = 0.021) resulted as risk factors of hemodynamic instability in our series. The use of intraoperative drugs was higher in patients with hemodynamic instability (p < 0.001). A pre-surgical SBP level of > 133 mmHg (OR = 6 CI95% 1.37-26.20, p = 0.017) and an intraoperative SBP and MBP levels of > 127 mmHg (OR = 28.80 CI95% 2.23-371.0, p = 0.010) and > 90 mmHg (OR = 18.90 CI95% 1.82-196.0, p = 0.014), respectively, were identified as effective thresholds to recognize patients at higher risk of HI.
CONCLUSIONS
A preoperative therapy with alpha-blockers is useful, but not sufficient to avoid surgical risks. Patients with higher pre-surgical levels of NMNur, pre-surgical SBP > 133 mmHg, and/or intraoperative SBP > 127 mmHg and MBP > 90 mmHg, should be carefully monitored. A multidisciplinary approach is indispensable to optimize the management of PHEOs/abdominal PGLs in order to reduce surgical complications.
Topics: Male; Female; Humans; Middle Aged; Pheochromocytoma; Retrospective Studies; Doxazosin; Normetanephrine; Paraganglioma; Hemodynamics; Adrenal Gland Neoplasms; Catecholamines; Vascular Diseases
PubMed: 37370080
DOI: 10.1186/s12957-023-03072-z -
International Journal of Molecular... Aug 2016This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to... (Review)
Review
This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Antineoplastic Agents; Doxazosin; Female; Humans; Male; Prazosin; Prostatic Neoplasms
PubMed: 27537875
DOI: 10.3390/ijms17081339 -
Current Research in Physiology 2022The autonomic profile of mice submitted to sustained hypoxia (SH) was not yet fully evaluated. Herein, we characterized the cardiovascular and autonomic profile of...
The autonomic profile of mice submitted to sustained hypoxia (SH) was not yet fully evaluated. Herein, we characterized the cardiovascular and autonomic profile of conscious freely moving mice submitted to SH using two sequential experimental protocols to evaluate the parasympathetic and sympathetic tone to the heart and the sympathetic tone to the vascular resistance. In the first protocol the sequence of antagonists was methyl-atropine followed by propranolol and then by prazosin, while in the second protocol the sequence was propranolol followed by methyl-atropine and then by prazosin. In SH the baseline heart rate was significantly lower than in control mice and the antagonism of the parasympathetic and sympathetic tone to the heart in both experimental protocols indicated an increased parasympathetic tone in SH mice and no changes in the sympathetic tone. Antagonism of the sympathetic tone to the vascular resistance with prazosin produced similar changes in arterial pressure in control and SH mice. Altogether these findings support the concept that mice submitted to SH present a significant increase in the parasympathetic but not in the sympathetic tone, which may explain why the baseline arterial pressure was not increased in SH mice.
PubMed: 36185816
DOI: 10.1016/j.crphys.2022.09.006 -
Experimental and Therapeutic Medicine Aug 2020Prazosin, an α-adrenergic receptor antagonist, is used to treat mild to moderate hypertension. It has recently been discovered that α-adrenergic receptors may have...
Prazosin, an α-adrenergic receptor antagonist, is used to treat mild to moderate hypertension. It has recently been discovered that α-adrenergic receptors may have potential antitumor properties. Therefore, in the present study, the effect of prazosin on human glioblastoma and the underlying mechanism were investigated. Human glioblastoma U251 and U87 cells were treated with different concentrations of prazosin, and a Cell Counting Kit-8 assay was performed to investigate the effects of prazosin on cell proliferation. Transwell migration and invasion assays were used to assess the effects of prazosin on cell migration and invasion. Prazosin-induced apoptosis in U251 and U87 cells was detected by flow cytometry, and the protein expression levels of anti-apoptotic proteins and proteins related to the PI3K/AKT/mTOR signaling pathway were detected by western blotting. The results suggested that following treatment with prazosin, the proliferation, migration and invasion of U251 and U81 cells were decreased. By contrast, U251 and U81 cell apoptosis, as well as the protein expression levels of Bax and active Caspase-3 were increased after prazosin treatment (P<0.05). Bcl-2 levels were also decreased after prazosin treatment (P<0.05). Additionally, the expression of phosphorylated (p)-AKT and p-mTOR, P70 and cyclin D1 were decreased in U251 and U81 cells following prazosin treatment (P<0.05). The present study suggested that prazosin may suppress glioblastoma progression by downregulating the activity of the PI3K/AKT/mTOR signaling pathway.
PubMed: 32765662
DOI: 10.3892/etm.2020.8772 -
Andrology Nov 2022Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such...
BACKGROUND
Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the α -adrenergic receptors such as doxazosin, tamsulosin, and prazosin.
OBJECTIVES
To investigate the liberation of 6-ND by human epididymal vas deferens (HEVDs) and its pharmacological actions.
METHODS
The in vitro liberation of 6-ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC-MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric-field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L-NAME and the release of catecholamines and the contractile response to EFS were assessed.
RESULTS
6-ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6-ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L-NAME reduced both the 6-ND release and the contractions induced by EFS.
DISCUSSION AND CONCLUSION
6-ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and α -adrenergic receptor antagonists.
Topics: Adrenergic Antagonists; Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Carbamazepine; Chromatography, Liquid; Desipramine; Dopamine; Doxazosin; Epinephrine; Humans; Male; Muscle Contraction; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Prazosin; Rats; Receptors, Adrenergic; Tamsulosin; Tandem Mass Spectrometry; Vas Deferens
PubMed: 35934935
DOI: 10.1111/andr.13263 -
Archives of Razi Institute Feb 2022The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first...
The current study was conducted to investigate the interaction between the central adrenergic and histaminergic systems and the broiler chick's feed intake. In the first experiment, the intracerebroventricular (ICV) injection of solutions was conducted which included 10 nmol of prazosin (an α-receptor antagonist), 300 nmol of histamine, co-injection of prazosin and histamine. Experiments two to five were conducted similarly the same as the first experiment, in which chickens were ICV injected with 13 nmol of yohimbine (an α-receptor antagonist), 24 nmol of metoprolol (a β adrenergic receptor antagonist), 5 nmol of ICI 118,551 (a β adrenergic receptor antagonist), and 20 nmol of SR 59230R (a β adrenergic receptor antagonist). The injected solutions in the sixth experiment included 300 nmol of noradrenaline, 250 nmol of α-FMH (an alpha fluoromethyl histidine), noradrenaline, and α-FMH. Seventh to ninth experiments were similar to the sixth experiment, except that the chickens were ICV injected with 300 nmol of chlorpheniramine (a histamine H receptors antagonist), 82 nmol of famotidine (a histamine H receptors antagonist), and 300 nmol of thioperamide (a histamine H receptors antagonist), rather than α-FMH. Afterward, the cumulative food intake was measured 120 min after injection. Based on the obtained results, both histamine ICV injection and noradrenaline injection reduced food intake (<0.05). Moreover, co-injection of histamine and ICI 118,551 (<0.05), and co-injection of noradrenaline and Chlorpheniramine reduced food intake (<0.05). In addition, noradrenaline and Thioperamide co-injection improved hypophagic effect of noradrenaline in neonatal chicken (<0.05). These findings suggested the effect of interconnection between adrenergic and histaminergic systems, which may be mediated by H and H histaminergic and β adrenergic receptors, on the regulation of food intake in the neonatal broiler chicken.
Topics: Adrenergic Agents; Adrenergic Antagonists; Animals; Animals, Newborn; Appetite; Chickens; Chlorpheniramine; Feeding Behavior; Histamine; Norepinephrine; Prazosin; Receptors, Adrenergic; Receptors, Histamine
PubMed: 35891757
DOI: 10.22092/ARI.2021.354450.1638